Inorganic phosphate (P.sub.i), a charged anion, is essential to bioenergetics, metabolic regulation, and bone and membrane structure. It is well known that P.sub.i homeostasis in the body depends primarily on mechanisms that govern the renal excretion of P.sub.i into the glomerular filtrate and its subsequent reabsorption against an electrochemical gradient via brush-border epithelial cells located in the proximal tubule of the kidney [J. Bonjour and J. Caverzasio, Reviews in Physiological Pharmacoloy, 100:161-214 (1985); V. W. Dennis, Phosphate homeostasis, in HANDBOOK OF PHYSIOLOGY, (S. Shultz, ed. 1991) at pages 1785-1815.] This transepithelial transport of P.sub.i is mediated, in part, by a transport system which is driven by the transmembrane Na.sup.+ gradient across the microvilli brush border membrane. However, it remains largely unknown how cells transport and regulate necessary the intracellular concentrations of P.sub.i, and the molecular events underlying this system. Experiments using isolated kidney tubules or brush-border membranes have shown that P.sub.i transport is rather complex, regulated not only by extracellular [P.sub.i ] but also by neurotransmitters such as catecholamines (for review see V. W. Dennis, supra), and by a variety of hormones and metabolic factors. Berndt and Knox, "Renal Regulation of Phosphate Excretion", in THE KIDNEY. PHYSIOLOGY AND PATHOPHYSIOLOGY, (D. W. Seldin and G. Giebisch, eds., 1991) at pages 1381-1396. Renal denervation, for example, decreases sodium and phosphate reabsorption. Norepinephrine released from nerve endings in proximity to renal tubules acts on the proximal tubule to increase phosphate reabsorption. In studies of isolated tubules, however, dopamine is shown to inhibit phosphate and sodium transport in the rabbit proximal tubule. Furthermore, several studies also show that depletion of extracellular P.sub.i or increased circulating levels of parathyroid hormone alter the activity and expression of transporter molecules or both.
Several recent reports have demonstrated that P.sub.i homeostasis significantly affects the central nervous system (CNS). Phosphate/calcium alterations in serum, for example, have been implicated in the etiology and pathogenesis of Alzheimer's diseases. Depletion of high energy phosphates (phosphocreatine) and ATP is thought to be part of the final common pathway mediating excitotoxic neuronal cell death secondary to a wide variety of insults. Tight coupling between P.sub.i transport and ATP production has been observed in many cells and tissues. Chronic P.sub.i depletion in vivo is associated with a significant reduction in the ATP content of polymorphonuclear leukocytes, platelets, and various tissues including kidney, heart, and skeletal muscle. A similar observation has been made in cultured peripheral vagal nerves. This reduction in intracellular ATP has been shown to be a direct consequence of the decrease in intracellular P.sub.i which occurs following P.sub.i depletion. In addition to its possible role in ATP biosynthesis, several lines of evidence have suggested that P.sub.i may be involved in neuronal signalling events. In this regard, a study using brain tissue has recently shown that physiological concentrations of P.sub.i can enhance the ATP-dependent binding of Ca.sup.++ to brain microsomes, resulting in a larger intracellular pool of Ca.sup.++ releasable by inositol triphosphate. Our recent work have demonstrated that &gt;90% P.sub.i transport in cortical neurons, which displays similar kinetic parameters to those reported for cultured kidney proximal tubule epithelial cells and membrane vesicles, are sodium dependent and that this Na.sup.+ -dependent transport system is regulated through a Na.sup.+ -dependent P.sub.i cotransporter. B. Ni, et al,, Proceedings of the National Academy of Sciences (U.S.A.), 91:5607-5611 (1994).
The present invention describes the cloning and characterization of a human brain Na.sup.+ -dependent P.sub.i cotransporter which is selectively expressed in discrete populations of neurons and glia. Fluorescent in situ hybridization (FISH) analysis demonstrates that this Na.sup.+ -dependent P.sub.i cotransporter is located in chromosome 19 (19q13.3) which has been linked to susceptible gene(s) for late onset Alzheimer's disease. M. Mullan and F. Crawford, Trends in Neurological Sciences, 16, 398-403 (1993). The characterization and treatment of physiological disorders ms hereby furthered.